Abdominal atherosclerosis is not a risk factor of nonocclusive mesenteric ischemia among critically ill patients: a propensity matching study

Background Although risk factors of occlusive acute mesenteric ischemia are well known, triggering factors of nonocclusive mesenteric ischemia (NOMI) remain unclear. Alongside to the known risk factors for NOMI, the role of atherosclerosis is not fully elucidated. The purpose of our study was to evaluate whether abdominal atherosclerosis is a risk factor for NOMI. Methods From January 2018 to December 2021, all consecutive patients admitted to the intensive care unit who underwent contrast-enhanced CT for suspicion of NOMI were evaluated for inclusion. Clinical and biological data at the time of the CT scan were retrospectively extracted from medical charts and reviewed by a single radiologist. The cohorts were matched by a 1:1 propensity score based on the patient clinical, biological data, and abdominal CT features associated with NOMI. Noncontrast CT acquisitions were used to calculate calcium scores of the abdominal aorta, celiac trunk, superior mesenteric artery (SMA), and common iliac artery according to the Agatston method. Analyses were performed before and after propensity score matching. Results Among the 165 critically ill patients included, 59 (36%) had NOMI. Before matching analysis, the SMA and total abdominal Agatston calcium scores were not different between patients without and with NOMI (52.00 [IQR = 0, 473] vs. 137.00 [IQR = 0, 259], P = 0.857, respectively, and 7253 [IQR = 1220, 21738] versus 5802 [IQR = 2075, 15,084]; P = 0.723). The results were similar after matching 38 patients with NOMI and 38 without: 153 [IQR = 0, 665] versus 85 [IQR = 0, 240] (P = 0.312) for the SMA calcium score, and 7915 [IQR = 1812, 21561] versus 4139 [IQR = 1440, 9858] (P = 0.170) for the total abdominal Agatston calcium score. Conclusion Our results suggest that atherosclerosis is not a risk factor for NOMI in critically ill patients.


Introduction
Acute mesenteric ischemia (AMI) is a life-threatening condition associated with a high risk of death [1,2]. AMI is defined by the association of mesenteric vascular insufficiency (which can be occlusive or nonocclusive) with ischemic gut injury (which can be reversible or irreversible when transmural necrosis *Correspondence: p1calame@chu-besancon.fr occurs). Mesenteric vessel occlusion has long been the sole cause of acute mesenteric ischemia. However, during the last decades, following the progression of care and postoperative monitoring, nonocclusive mesenteric ischemia (NOMI) has emerged [3]. NOMI is a specific etiology of AMI characterized by intestinal ischemia without arterial blood vessel occlusion [4,5].
Risk factors of occlusive mesenteric ischemia are well known [6]: stagnant blood flow, hypercoagulability, and vascular alterations for venous OMI; heart failure, atrial fibrillation, coronary heart disease, arterial hypertension, and peripheral vascular disease for arterial OMI. Triggering factors of NOMI are not so well known. It is considered that the severity of shock per se could lead to NOMI among critically ill patients [7][8][9]. Hence, duration of low flow state and catecholamine infusion are established risk factors of NOMI. Two additional risk factors have been recently described [10]: enteral nutrition, which can be considered as a stress effort on the gut, and the low cardiac output and; thus, decreased oxygen delivery to the gut, highlighted by dobutamine requirement.
Alongside these risk factors, several studies have considered pre-existing abdominal atherosclerosis an evident risk factor of NOMI [11][12][13], favoring diminution of mesenteric flow and thus decreasing the oxygen supply to the gut. However, in-depth analysis of these studies either shows that atherosclerosis is not a risk factor in univariate analysis in the first place [8] or that it is no longer statistically significant in multivariate analysis [12,14]. Furthermore, most of these studies focused on NOMI in the postoperative setting of cardiac surgery, whereas the etiologies of NOMI include all conditions in which a persistent low-flow state may be occurring. In addition, the assumed relationship between catecholamine infusion, vessel vasoconstriction, and NOMI is unclear. On the one hand, atherosclerosis could be considered as an additional risk factor for gut ischemia, but on the other hand, atherosclerosis may also limit the capacity of small vessels for vasocontraction. In addition, atherosclerosis could favor the development of collateral arteries from angiogenesis; thus, limiting the risk of bowel ischemia [15].
Abdominal computed tomography (CT) remains the cornerstone of NOMI diagnosis, allowing the diagnosis of bowel transmural necrosis [7] and providing prognostic elements for these patients [16]. CT also allow quantification of atheroma by detecting vascular calcifications which has been extensively studied in the coronary arteries [17,18] by the Agatston method. However, quantification of calcification is not only possible on coronary arteries but on all arteries, and thus on arteries that supply blood to the gut [19].
Thus, we aimed to assess whether pre-existing abdominal atherosclerosis, especially when localized on mesenteric vessels, is a risk factor for nonocclusive mesenteric ischemia in critically ill patients.

Patients
This was a monocentric retrospective study conducted from January 1, 2018, to December 31, 2021. All consecutive patients from ICU who underwent an abdominal CT for suspicion of NOMI were evaluated for inclusion. The inclusion criteria were: (1) critically ill patient requiring hospitalization in the ICU, (2) an available pre-and post-contrast abdominal CT. Patients with an aortic endoprosthesis and patients without available noncontrast abdominal CT were excluded because of the impossibility of computing the calcium score. Our institutional review board approved this single-center retrospective study with a waiver of informed consent. The final study population included 165 patients (Fig. 1).

CT protocol
CT examinations were performed with a 128 MD CT scanner (Somatom Definition 128, Siemens Healthcare). In routine practice, the CT protocol for NOMI suspicion comprised noncontrast and multiphase contrast-enhanced acquisitions in the early arterial phase (acquired with bolus tracking, with a ROI located in the aorta) and portal venous phase (80 s after contrast administration). Contrast administration was performed by intravenous injection of 1.5 mL/kg of nonionic contrast medium at 400 mg I/mL through a power injector at a rate of 3-5 mL/s.

Imaging analysis
Abdominal CT scans were blindly reviewed by a single radiologist (BLINDED) with five years of experience in the field of abdominal imaging. Noncontrast acquisitions were imported onto an AW workstation (GE Healthcare, Chicago, Illinois) to calculate the calcium scores of the abdominal aorta, celiac trunk, superior mesenteric artery (SMA), and common iliac arteries using Smartscore 4.0 software (GE Healthcare) according to the Agatston method [20]. The abdominal aorta was defined as the segment from the diaphragm to the iliac bifurcation. Ostial calcifications of the celiac trunk and the superior mesenteric artery were included in the respective arteries (celiac trunk or superior mesenteric artery).
A single radiologist blinded from the final diagnosis of NOMI measured the maximal diameter of the superior mesentery artery, celiac trunk, and inferior mesentery artery. Stenosis of the celiac trunk and superior mesenteric artery were evaluated by the NASCET method [21] using multiplanar reconstructions on a PACS workstation (Carestream Health, Rochester, NY). Vessels stenosis were considered as nonsignificant, mild, moderate and severe when they were < 25%; ≥ 25%/ < 50%; ≥ 50%/ < 70 %, and ≥ 70%, respectively. Concerning the lower mesenteric artery, its small size precluded the reliable calculation of a calcium score or percentage stenosis, and thus, the diameter of its origin and the presence of stenosis or occlusion were recorded.
Reader also assessed the following CT features known to be associated with shock: spleen infarction, liver infraction, kidneys infarction, hyperenhancement of adrenal gland in the arterial phase, flattened vena cava, and diffuse splanchnic vasoconstriction.

Endpoint measures and data collected
NOMI was defined as the evidence of bowel ischemic injury at surgical exploration or digestive endoscopy in the absence of acute mesenteric vessel obstruction. In patients without surgical or endoscopic exploration, NOMI was diagnosed when abdominal CT showed evidence of ischemic bowel injury: absence of enhancement of the bowel wall ± thinned wall for small bowel  [7] and absence of enhancement of the bowel wall for the colonic involvement [22].
The data were retrospectively extracted from the patients' medical charts. Patients' characteristics, comorbidities, and clinical data were recorded at the time of the CT. Catecholamine infusion (norepinephrine, dobutamine use) and enteral nutrition were recorded as there are known NOMI risks factors. Blood tests, blood gas were recorded at the time of the CT. The main known risk factors for NOMI are summarized in Table 1.

Statistical analysis
Categorical data are expressed as numbers and percentages and were compared by Pearson chi-square or Fisher's exact test. Continuous variables are expressed as mean, standard deviation or median, interquartile range (IQR), and were compared using Student's t-test when the distribution was normal or the Wilcoxon test when the distribution was not normal.
All calcium scores and percent stenosis are described as non-normal continuous variables. A total abdominal calcium score was calculated as the sum of the scores from the aorta, celiac trunk, mesenteric, right, and left common iliac arteries.
Patients with and without NOMI were then matched 1:1 based on their propensity scores, using the nearest neighbor method and a caliper width of 0.1 standard deviations for the propensity score. The propensity score was calculated using a multivariate logistic regression that included the main known risk factors of NOMI (noradrenaline dose and lactate levels), significant biological variables (serum pH and bicarbonate levels), and CT features of low flow state associated with NOMI (adrenal gland hyperenhancement, diffuse splanchnic vasoconstriction, and superior mesentery artery maximal diameter).
All tests were two-sided, and a P value < 0.05 was considered statistically significant. All analyses were performed with R version 3.4.4 (R Core Team 2017).

Propensity score matching
The standardized mean differences (SMD) of all clinical and biological variables input into the multivariate model were < 0.20 after propensity score matching (i.e., noradrenaline dose, lactate level, bicarbonate level, pH) ( Table 3). All SMD of adjusted CT variables input into the multivariate model were also < 0.20 after PSM (propensity score matching) (i.e., presence of diffuse vasosplanchnic vasoconstriction, adrenal gland hyperenhancement, flat inferior vena cava, liver infarction, kidney infarction, spleen infarction, and superior mesenteric artery diameter). The area under the ROC curve (AUROC) of the propensity score for the prediction of NOMI was 0.79 (95%CI 0.71-0.86). Performances and density plots of the propensity score before and after propensity score are presented in Fig. 2.

Atherosclerosis and NOMI
Before PSM, the 59 patients with confirmed NOMI showed no difference in overall atherosclerosis burden compared with those without NOMI ( Table 4). The calcium score of the SMA was not different between groups (median 52 [IQR = 0, 473] in patients without NOMI vs. 137 [IQR = 0, 259] in patients with NOMI, P = 0.857 (Fig. 3). The percentage of SMA stenosis was not different between patients without or with NOMI

Discussion
This study aimed to assess the relationship between preexisting abdominal atherosclerosis and NOMI in critically ill patients. After propensity score matching analysis Table 3 Characteristics of the study population at the time of the CT before and after propensity score matching Numbers in brackets are percentages for qualitative variables Non-normal quantitative variables are expressed as median and interquartile range and compared using Wilcoxon-Test Normal quantitative variables are expressed as mean ± standard deviation and compared using student test Bold value are variables included in the propensity matched analysis CT computerized tomography, NOMI nonocclusive mesenteric ischemia, ASAT aspartate aminotransferase, PaCO 2 arterial blood carbon dioxide tension, PaO 2 arterial blood oxygen tension, SD standard deviation, PT prothrombin rate, SMD Standard mean deviation n Before propensity score matching P value SMD After propensity score matching P value SMD  . 2 A ROC curve of the propensity score for nonocclusive mesenteric ischemia prediction. B Density plot shows the propensity score distribution before propensity score matching analysis. C Density plot shows the propensity score distribution after propensity score matching analysis according to the main known risk factors of NOMI and CT features of low flow state, we showed that abdominal atherosclerosis, especially when localized on mesenteric vessels, is not a risk factor for NOMI. The relationship between NOMI and abdominal atherosclerosis is challenging to elucidate. Previous studies evaluated only "peripheral atherosclerosis disease" [9,13,14] as an atherosclerosis marker. Even if this marker was associated with the development of NOMI, mainly in the context of cardiac surgery, it does not qualify atherosclerosis as a risk factor for NOMI but may reflect confusion biases. Indeed, the postoperative course after cardiac surgery may be more complicated in a patient with pre-existing atherosclerosis, with no role for atherosclerosis per se in developing NOMI. For example, Nilsson et al. [12] showed that peripheral arterial disease was a risk factor for NOMI after cardiac surgery in univariate analysis (present in 2388/18862 (13%) vs. 7/17 (41%) of patients without vs. patients with NOMI; P < 0.001). However, the multivariate analysis identified only postoperative features as being significantly associated with NOMI and excluded atherosclerosis.

Absence of NOMI Presence of NOMI Absence of NOMI Presence of NOMI
We specifically evaluated atherosclerosis of the mesenteric vessels. Furthermore, as the calcium score imperfectly characterizes the atherosclerotic disease burden, we also evaluated other parameters such as stenosis of the mesenteric vessels. None were found associated with NOMI. Indeed, after PSM analysis of critically ill patients with comparable levels of visceral failure, low flow, and catecholamine doses, we observed similar atherosclerosis burden, by calcium score, but also percentage of mesenteric vessels stenosis evaluation. Further studies should now focus on the prognostic value of atherosclerosis in critically ill patients. Although atherosclerosis is a risk factor for poor outcomes in patients with NOMI [19], it does not seem to play a specific role in the occurrence of NOMI. Therefore, NOMI should be suspected in view of the severity of shock and low-flow states, high dose of catecholamines, marked lactic acidosis, increased plasma creatinine, and hepatic failure more than pre-existing cardiovascular risk factors or atheromatous burden.
Other factors are associated with NOMI. First, we found that all CT features belonging to the hypoperfusion complex [19,20,23], i.e., the hollow adrenal gland sign [24], organ infarction, flattened inferior vena cava, vasoconstriction of mesenteric vessels [5,[25][26][27] were all associated with NOMI. Indeed, NOMI is the ultimate consequence of prolonged gut hypoperfusion and has a poor prognosis. Abdominal CT has a major role as an initial diagnostic modality in abdominal emergencies [28][29][30], but also in critically ill patients [7,22] by detecting bowel ischemia and necrosis. Further studies will now have to focus on earlier steps of gastro-intestinal failure such as such as a potential correlation between CT features and biomarkers of endothelial dysfunction [31], but also with biomarkers Fig. 3 Boxplots of the distribution (median and interquartile range) of superior mesenteric artery and total abdominal calcium score according to nonocclusive mesenteric ischemia. Lines are median and interquartile range. A Before propensity score matching analysis. B After propensity score matching analysis. SMA Superior mesenteric artery of mucosal gut damage [32], and their association with intra-abdominal pressure. To this end, in assessing changes in microcirculation along the gut in critically ill patients, dual-energy CT will certainly have a role to play in quantifying the change in vascularity by iodinate concentration measurement.
Our study has limitations. First, this retrospective study is subject to a selection bias. Indeed, we included only patients with NOMI suspicion and an available enhanced abdominal which have selected a very poor prognosis cohort that suffer from multiorgan failure, with high prevalence of atherosclerosis. Although performance of propensity score was good, matching analysis on other severity scores could have strengthened PSM. Then, a relatively high proportion of our cohort (i.e., 24/59; 41%) did not have surgical or endoscopic confirmation of NOMI due to their poor prognosis. However, our group previously identified reliable CT findings of NOMI [7,18], and we believe that the risk of underdiagnosis of NOMI remains low (Specificity of absence of enhancement range from 79 to 97% according to the bowel segment involved [22]). Because of the time required by the calculation of abdominal calcium scores, the number of patients in the study is relatively limited. Thus, prevalence of significant mesenteric vessels stenosis is low, and study may be underpowered. Finally, morphologic CT evaluation may not reflect the hemodynamic change induce by vessels stenosis.
In conclusion, our results suggest that the calcium score and stenosis of the three main mesenteric arteries are not associated with an increased risk of NOMI. The main factors associated with NOMI are related to the severity and the duration of shock but are not related to the abdominal atherosclerosis burden.